Racemic beta-hydroxybutyrate mixed salt-acid compositions and methods of use

ABSTRACT

Ketogenic compositions include a racemic mixture of R- and S-beta-hydroxybutyric acids and a racemic mixture of R- and S-beta-hydroxybutyrate salts. The compositions contain the R-enantiomer to elevate ketone bodies and increase the rate at which ketosis is achieved and yet contain an equivalent amount of the S-enantiomer to provide alternative benefits. The R- and S-beta-hydroxybutyric acids are more rapidly absorbed and utilized by the body than salts or esters, enhance taste, and reduce the need to include citric acid or other edible acids. The R- and S-beta-hydroxybutyrate salts are more slowly absorbed and utilized by the body and can provide one or more electrolytes. The ketogenic composition may contain a dietetically or pharmaceutically acceptable carrier and a racemic mixture of R- and S-beta-hydroxybutyrate salts and acids. The composition contains less than 100% by molar equivalents of total R,S-beta-hydroxybutyrate salts and more than 0% by molar equivalents of R,S-beta-hydroxybutyric acids.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application claims the benefit of U.S. Provisional PatentApplication No. 62/805,054, filed Feb. 13, 2019, the disclosure of whichis incorporated by reference in its entirety.

BACKGROUND 1. Field of The Invention

Disclosed herein are racemic beta-hydroxybutyrate compounds,particularly salts and acids of racemic beta-hydroxybutyrate, andmethods of administering racemic beta-hydroxybutyrate mixed salt-acidcompositions for producing elevated blood levels of ketone bodies in asubject.

2. Related Technology

In periods of fasting, extreme exercise, and/or low carbohydrateconsumption, glucose and glycogen stores in the body are rapidly usedand can become quickly depleted. Failure to replenish glucose stores asthey become depleted causes the body to metabolically shift to thecreation and use of ketone bodies for energy (“ketosis”). Ketone bodiescan be used by cells of the body as a fuel to satisfy the body's energyneeds, including the brain and heart. During prolonged fasting, forexample, blood ketone levels can increase to 2-3 mmol/L or more. It isconventionally understood that when blood ketones rise above 0.5 mmol/L,the heart, brain and peripheral tissues are using ketone bodies (e.g.,beta-hydroxybutyrate and acetoacetate) as the primary fuel source. Thiscondition is referred to as ketosis. At blood levels between 1.0 mmol/Land 3.0 mmol/L the condition is called “nutritional ketosis.”

Upon transitioning into ketosis, or in other words, during ketogenicmetabolism in the liver, the body uses dietary and bodily fats as aprimary energy source. Consequently, once in ketosis, one can induceloss of body fat by controlling dietary fat intake and maintaining lowcarbohydrate intake and blood level to sustain ketosis.

During ketosis, the body is in ketogenesis and essentially burning fatfor its primary fuel. The body cleaves fats into fatty acids andglycerol and transforms fatty acids into acetyl CoA molecules, which arethen eventually transformed through ketogenesis into the water-solubleketone bodies beta-hydroxybutyrate (i.e., “β-hydroxybutyrate” or “BHB”),acetoacetate (also known as acetylacetonate), and acetone in the liver.Beta-hydroxybutyrate and acetoacetate are the primary ketone bodies usedby the body for energy while acetone is removed and expelled as aby-product of ketogenesis.

The metabolism of ketone bodies is associated with several beneficialeffects, including anticonvulsant effects, enhanced brain metabolism,neuroprotection, muscle sparing properties, and improved cognitive andphysical performance. Science-based improvements in efficiency ofcellular metabolism, managed through ketone supplementation, can havebeneficial impacts on physical, cognitive health, and psychologicalhealth, and a long-term impact on health with respect to commonavoidable diseases such as obesity, cardiovascular disease,neurodegenerative diseases, diabetes, and cancer.

Despite the many health advantages of pursuing a ketogenic diet orlifestyle and maintaining a state of nutritional ketosis, there remainsignificant barriers to pursuing and maintaining a ketogenic state. Oneof these barriers is the difficulty of transitioning into a ketogenicstate. The fastest endogenous way to enter ketosis is by depletingglucose stores in the body through fasting combined with exercise. Thisis physically and emotionally demanding and is extremely challengingeven for the most motivated and disciplined.

Additionally, the transition into ketosis is often accompanied byhypoglycemia, which can cause lethargy and light-headedness in many,resulting in an uncomfortable physiological and mental state commonlyreferred to as the “low-carb flu.” In addition, many people experience adown regulation in their metabolism as the body naturally goes into an“energy-saving” mode. Some suggest that these transitory symptoms maylast as long as two to three weeks. During this transition period, if asubject consumes a meal or snack containing carbohydrates above therestrictive amount, there is an immediate termination of ketogenesis,exiting the body from its state of ketosis. The body then shifts back toglucose utilization for its primary fuel and the transition into ketosismust begin anew.

If a subject is successful in establishing ketosis, the act ofsustaining ketosis is likewise difficult, if not more difficult, due tothe need to maintain a rigid dietary ratio of carbohydrates and proteinto fats. It is further complicated by the disruption of normalelectrolyte balances that often occurs when transitioning into andmaintaining a ketogenic state. The depletion and lowering of glycogenstores in the liver and muscles lessens the ability of the body toretain water, leading to more frequent urination, and accordingly, agreater loss of electrolytes. Further, the reduction in insulin levelscaused by ketosis effects the rate at which certain electrolytes areextracted by the kidneys, which can additionally lower electrolytelevels in the body. Negative effects of electrolyte imbalance includemuscle aches, spasms, twitches and weakness, restlessness, anxiety,frequent headaches, feeling very thirsty, insomnia, fever, heartpalpitations or irregular heartbeats, digestive issues such as cramps,constipation or diarrhea, confusion and trouble concentrating, bonedisorders, joint pain, blood pressure changes, changes in appetite orbody weight, fatigue (including chronic fatigue syndrome), numbness injoints, and dizziness, especially when standing up suddenly.

Some compositions used to promote ketosis in a mammal include thosedisclosed in U.S. Patent Publication No. 2017/0296501 to Lowery et al.,which contain the endogenous form of beta-hydroxybutyrate, orR-beta-hydroxybutyrate, while Lowery et al. discourage use of thenon-endogenous enantiomer, or S-beta-hydroxybutyrate, and racemicmixtures of R-and S-beta-hydroxybutyrate. Others, such as thosedisclosed in U.S. Pat. No. 8,642,654 to Clarke et al. consist mostly orentirely of a single beta-hydroxybutyrate ester (3R)-hydroxybutyl(3R)-hydroxybutyrate. The omission of enantiomers that are not theendogenous form of beta-hydroxybutyrate is based on the view thatS-beta-hydroxybutyrate (aka (3S)-hydroxybutyrate) is ineffective or evenharmful.

BRIEF SUMMARY

Disclosed herein are racemic R,S-beta-hydroxybutyrate mixed salt-acidcompositions and methods of use in increasing ketone body level in asubject, including promoting and/or sustaining ketosis in a subject overan extended period of time.

The racemic R,S-beta-hydroxybutyrate mixed salt-acid compositionsdisclosed herein comprise a racemic mixture of R-beta-hydroxybutyratesalt(s) and S-beta-hydroxybutyrate salt(s) (“R,S-beta-hydroxybutyratesalts”) and a racemic mixture of R-beta-hydroxybutyric acid andS-beta-hydroxybutyric acid (“R,S-beta-hydroxybutyric acids”). A “racemicmixture” of R,S-beta-hydroxybutyrate salts includes enantiomericallyequivalent amounts (50:50) of R- and S-beta-hydroxybutyrate salts. A“racemic mixture” of R,S-hydroxybutyric acids includes enantiomericallyequivalent amounts (50:50) of R- and S-beta-hydroxybutyric acids.

R-beta-hydroxybutyrate is the endogenous form produced by a mammal, andS-beta-hydroxybutyrate enters the body through exogenous supplementationthrough the administration of a racemic RS-beta-hydroxybutyrate mixedsalt-acid composition. The racemic RS-beta-hydroxybutyrate mixedsalt-acid composition thus includes separate components which functiondifferently in the body but together provide enhanced ketogenic effects,including greater sustained blood ketone levels compared to theadministration of only R-beta-hydroxybutyrate compounds. TheR,S-beta-hydroxybutyrate mixed salt-acid compositions provide at least a“double racemic stack” of beta-hydroxybutyrate compounds.

The R-beta-hydroxybutyrate enantiomer is endogenously produced by amammal during ketosis, and the exogenously administeredR-beta-hydroxybutyrate mixed salt-acid components thus provide anadditional quantity and/or increased blood plasma level ofR-beta-hydroxybutyrate that can be immediately utilized by the body,such as for producing energy (e.g., as an alternative energy source toglucose). The S-beta-hydroxybutyrate components, which are notendogenously produced by a mammal, complement the R-beta-hydroxybutyratecomponents, and produce one or more desired effects in the mammal notproduced by the R-beta-hydroxybutyrate components.

For example, administering the S-beta-hydroxybutyrate mixed salt-acidcomponents along with the R-beta-hydroxybutyrate mixed salt-acidcomponents in enantiomerically equivalent ratios can result in at leastone of: (1) increased endogenous production of R-beta-hydroxybutyrateand acetoacetate; (2) endogenous conversion of theS-beta-hydroxybutyrate components into one or both ofR-beta-hydroxybutyrate and acetoacetate; (3) endogenous conversion ofthe S-beta-hydroxybutyrate components into fatty acids and sterols; (4)prolonged ketosis; (5) metabolism of the S-beta-hydroxybutyratecomponents independent of conversion to R-beta-hydroxybutyrate and/oracetoacetate; (6) increased fetal development; (7) increased growthyears; (8) reduced endogenous production of acetone during ketosis; (9)signaling by the S-beta-hydroxybutyrate components that modulatesmetabolism of R-beta-hydroxybutyrate and glucose; (10) antioxidantactivity; and (11) production of acetyl-CoA.

By way of further example, exogenous delivery of a racemicR,S-beta-hydroxybutyrate mixed salt-acid composition can beneficiallyprovide a relatively rapid boost to blood ketone body levels, primarilyby way of the R-beta-hydroxybutyrate mixed salt-acid components,particularly R-beta hydroxybutyric acid, in addition to a relativelymore sustained addition to blood ketone body level primarily by way ofthe S-beta-hydroxybutyrate mixed salt-acid components. Such racemicR,S-beta-hydroxybutyrate mixed salt-acid compositions are thus capableof effectively and relatively rapidly aiding a subject in inducingketosis, while simultaneously providing for sustained and prolongeddelivery of ketone bodies to the blood stream by virtue of themodulating effects of the S-beta-hydroxybutyrate mixed salt-acidcomponents in providing ketogenic benefits as required by the body.

Combining R,S-beta-hydroxybutyric acid with one or moreR,S-beta-hydroxybutyrate salts is highly beneficial because it reduceselectrolyte load, increases absorption rate, improves taste, facilitateseasier formulation, and reduces the need to add citric acid or otheredible acids to obtain a composition having neutral or acidic pH.

In some embodiments, the racemic R,S-beta-hydroxybutyrate mixedsalt-acid compositions described herein may be combined with (e.g.,directly admixed with or co-administered with) one or more otherdietetically and/or pharmaceutically acceptable supplements/drugs toform a combination supplement. The unique properties of a racemicR,S-beta-hydroxybutyrate mixed salt-acid composition may beneficiallyenhance the combination supplement as compared to an otherwise similarcombination supplement using a beta-hydroxybutyrate compositionconsisting of or enriched with either R-beta-hydroxybutyrate orS-beta-hydroxybutyrate. For example, a composition intended to increaselipolysis and/or fat oxidation (referred to herein as a “fat burner”component) may be combined with a racemic R,S-beta-hydroxybutyrate mixedsalt-acid composition to form a combination supplement with synergisticlipolysis and/or fat burning effects. In another example, a compositionintended to increase enhance mental alertness, cognition, and/or mood(referred to herein as a “nootropic” component) may be combined with aracemic R,S-beta-hydroxybutyrate mixed salt-acid composition to form acombination supplement with synergistic cognitive, alertness, and/ormood effects.

In some embodiments, the racemic R,S-beta-hydroxybutyrate mixedsalt-acid compositions disclosed herein can be used in a method forincreasing ketone body level in a subject, including promoting and/orsustaining ketosis in a subject, comprising administering to a subjectin need thereof a nutritionally or pharmaceutically effective amount ofone or more compositions disclosed herein. Examples of beneficialeffects of increased ketone body level in a subject include one or moreof appetite suppression, weight loss, fat loss, reduced blood glucoselevel, improved mental alertness, anxiolytic effects (anti-anxiety),faster reaction time, increased physical energy, improved cognitivefunction, reduction in traumatic brain injury, reduction in effect ofdiabetes, improvement of neurological disorder, reduction of cancer,reduction of inflammation, anti-aging, antiglycation, reduction inepileptic seizer, improved mood, increased strength, increased musclemass, or improved body composition.

In some embodiments, the composition may include a nutritionally orpharmaceutically acceptable carrier.

Embodiments include a “racemic stack” of at least four differentbeta-hydroxybutyrate compounds. R-beta-hydroxybutyrate andS-beta-hydroxybutyrate are provided as free acids (i.e.,R-beta-hydroxybutyric acid and S-beta-hydroxybutyric acid), saltsthereof (i.e., R-beta-hydroxybutyrate salt(s) and S-beta-hydroxybutyratesalt(s)), and optionally esters thereof (i.e., R-beta-hydroxybutyrateester(s) and S-beta-hydroxybutyrate ester (s)). Providingbeta-hydroxybutyrate as a double racemic stack that combines at leastfour separate forms (or triple racemic stack that combines six separateforms) of beta-hydroxybutyrate may beneficially allow the use of higheramounts of beta-hydroxybutyrate for a given administered dose and/orallow for more doses per day. Each form of beta-hydroxybutyrate istypically associated with its own particular positive attributes andnegative side effects. Stacking different forms of beta-hydroxybutyrateallows for delivery of more of the positive attributes compared to eachbeing used alone. Similarly, stacking different forms ofbeta-hydroxybutyrate reduces or mitigates the negative side effects ofeach particular form of beta-hydroxybutyrate so that such negativeeffects can be “spread-out” and limited. In either case, stackingincreases or maximizes the overall dose of beta-hydroxybutyrate that canbe efficaciously delivered.

Additional features and advantages will be set forth in part in thedescription that follows, and in part will be obvious from thedescription, or may be learned by practice of the embodiments disclosedherein. It is to be understood that both the foregoing brief summary andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the embodiments disclosed herein or asclaimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A illustrates higher levels of the amount of beta-hydroxybutyrateadministered when using a “stacked” dose of at least two different formsof racemic R,S-beta-hydroxybutyrate as compared to single forms ofracemic R,S-beta-hydroxybutyrate;

FIG. 1B illustrates expected relative rates of undesirable side-effectsresulting from treatment with various formulations ofbeta-hydroxybutyrate, where a “double stack” (i.e., double racemicstack) formulation comprising 1) free R,S-beta-hydroxybutyric acids and(2) R,S-beta-hydroxybutyrate salts and a “triple stack” (i.e., tripleracemic stack) formulation further comprising R,S-beta-hydroxybutyricesters on top of the double stack are expected to allow foradministration of greater amounts of beta-hydroxybutyrate and/or reducedoccurrences or intensities of side-effects as compared to administeringsingle forms of beta-hydroxybutyrate;

FIG. 2 compares expected release profiles of R,S-beta-hydroxybutyratestack compositions to free acid, salt, and ester single forms and alsoan R-beta-hydroxybutyrate stack, illustrating that stackedR,S-compositions provide an overall release profile that is extended andhas a larger area under the curve (AUC); and

FIG. 3 illustrates expected relative rates of lipolysis and/or fatoxidation resulting from treatment with a combination weight losssupplement including a beta-hydroxybutyrate component in combinationwith another weight loss supplement, and showing total amount oflipolysis and/or fat oxidation (area under the curve) is higher for acombination supplement using racemic R,S-beta-hydroxybutyrate componentsas compared to otherwise similar combination supplements/drugs usingbeta-hydroxybutyrate components enriched in R-beta-hydroxybutyrate orS-beta-hydroxybutyrate.

DETAILED DESCRIPTION I. Definitions

The compound “beta-hydroxybutyrate,” also known as β-hydroxybutyrate,3-hydroxybutyrate, βHB, or BHB, is the deprotonated form ofbeta-hydroxybutyric acid, which is a hydroxycarboxylic acid having thegeneral formula CH₃CH₂OHCH₂COOH. The deprotonated form present attypical biological pH levels is CH₃CH₂OHCH₂COO⁻. The general chemicalstructure shown below represents beta-hydroxybutyrate compounds that maybe utilized in the disclosed compositions:

-   where,-   X can be hydrogen, metal ion, amino cation such as from an amino    acid, alkyl, alkenyl, aryl, or acyl.

When X is a hydrogen, the compound is beta-hydroxybutyric acid. When Xis a metal ion or an amino cation, the compounds is abeta-hydroxybutyrate salt. When X is alkyl, alkenyl, aryl, or acyl, thecompounds is a beta-hydroxybutyrate ester. The foregoing compounds canbe in any desired physical form, such as crystalline, powder, solid,liquid, solution, suspension, or gel.

The term “racemic R,S-beta-hydroxybutyrate” means there areenantiomerically equivalent amounts (50:50) of total R- andS-beta-hydroxybutyrate in the composition. The terms “racemicR,S-beta-hydroxybutyrate salt” and “racemic R,S-beta-hydroxybutyratesalts” mean there are enantiomerically equivalent amounts (50:50) oftotal R- and S-beta-hydroxybutyrate salts in the composition. The term“racemic R,S-beta-hydroxybutyric acid” means there are enantiomericallyequivalent amounts (50:50) of R- and S-beta-hydroxybutyric acids in thecomposition. The terms “racemic R,S-beta-hydroxybutyrate ester” and“racemic R,S-beta-hydroxybutyrate esters” mean there areenantiomerically equivalent amounts (50:50) of total R- and S-beta-hydroxybutyrate esters in the composition.

The term “R,S-beta-hydroxybutyrate mixed salt-acid composition” meansthere are enantiomerically equivalent amounts of one or moreR-beta-hydroxybutyrate salts and one or more S-beta-hydroxybutyratesalts in the composition, and there are enantiomerically equivalentamounts (50:50) of free R-beta-hydroxybutyric acid and freeS-beta-hydroxybutyric acid in the composition.

The term “R,S-beta-hydroxybutyrate salt” does not mean or imply anyparticular physical state, such as a crystalline, powder, other solidform, dissolved in water to form a liquid solution, dispersed in aliquid to form a suspension, or gel. A salt can be formed in solution,such as by at least partially neutralizing beta-hydroxybutyric acid witha strong or weak base, such as an alkali or alkaline earth metalhydroxide, carbonate, or bicarbonate, basic amino acid, and the like.

The term “free beta-hydroxybutyric acid” means the sum ofnon-deprotonated and deprotonated beta-hydroxybutyric acid molecules. Adeprotonated beta-hydroxybutyric acid molecule generally means amolecule that has released a proton to form a hydronium ion (H₃O+) and abeta-hydroxybutyrate anion (e.g., dissolved in water).

Free beta-hydroxybutyric acid molecules are typically not deprotonatedto any significant degree when contained in a beta-hydroxybutyrate mixedsalt-acid composition in dry powder or other solid form. In such cases,the fractional amount of free beta-hydroxybutyric acid in abeta-hydroxybutyrate mixed salt-acid composition on a weight basis isthe weight of free beta-hydroxybutyric acid divided by the combinedweight of free beta-hydroxybutyric acid and beta-hydroxybutyratesalt(s). On a molar basis, the fractional amount of freebeta-hydroxybutyric acid in an beta-hydroxybutyrate mixed salt-acidcomposition are the molar equivalents of free beta-hydroxybutyric aciddivided by the sum of molar equivalents of free beta-hydroxybutyric acidand beta-hydroxybutyrate anions provided by the beta-hydroxybutyratesalt(s).

When dissolved in water, a portion of the beta-hydroxybutyric acid willtypically dissociate into beta-hydroxybutyrate anions and hydronium ions(H₃O+). As a result, beta-hydroxybutyric acid molecules can exchangeprotons and cations with dissolved beta-hydroxybutyrate salts. Forpurposes of defining the relative amounts of beta-hydroxybutyric acidand beta-hydroxybutyrate salt(s) in a beta-hydroxybutyrate mixedsalt-acid composition, dissociation of beta-hydroxybutyric acidmolecules and the exchange of protons and cations is not understood aschanging the molar ratio of free beta-hydroxybutyric acid relative tobeta-hydroxybutyrate anions from the beta-hydroxybutyrate salt(s). Thetotal quantity of free beta-hydroxybutyric acid molecules in solution isthe sum of dissolved beta-hydroxybutyric acid molecules that are notdeprotonated and beta-hydroxybutyrate anions formed by deprotonation ofbeta-hydroxybutyric acid molecules.

Stated another way, the total molar equivalents of beta-hydroxybutyricacid in solution, whether or not deprotonated, is understood to be thedifference between (i) the sum of molar equivalents of non-deprotonatedbeta-hydroxybutyric acid molecules and total molar equivalents ofbeta-hydroxybutyrate anions in solution (from all sources) and (ii) thetotal molar equivalents of cationic charge provided by cations from thebeta-hydroxybutyrate salt compounds (which equals the total molarequivalents of beta-hydroxybutyrate anions provided by thebeta-hydroxybutyrate salt(s)). Alkali metal cations such as sodium andpotassium provide 1 mole of cationic charge per mole of metal cations.Alkaline earth metal cations such as magnesium and calcium, on the otherhand, provide 2 moles of cationic charge per mole of metal cations. 1mole of deprotonated beta-hydroxybutyric acid molecules provide 1 moleof anionic charge and one mole of cationic charge.

In view of the foregoing, the molar fraction of beta-hydroxybutyric acidin solution in relation to total moles of beta-hydroxybutyrate moleculesfrom the beta-hydroxybutyrate mixed salt-acid composition in solution is[(i)-(ii)÷(i)], and the molar fraction of beta-hydroxybutyrate moleculesfrom the beta-hydroxybutyrate salt(s)) in solution is [(ii)÷(i)].Multiplying the molar fraction of each by 100 gives the percentage ofeach in solution.

By way of example, if 100 molar equivalents of beta-hydroxybutyratemixed salt-acid composition in a dry powdered state contained 5% of freenon-deprotonated beta-hydroxybutyric acid and 95% beta-hydroxybutyratesalt(s) on a molar basis, there would be essentially 5 molar equivalentsof beta-hydroxybutyric acid molecules and 95 molar equivalents ofbeta-hydroxybutyrate anions. When there is sufficient water to dissolvethe beta-hydroxybutyrate salt(s), and if a portion of thebeta-hydroxybutyric acid molecules were deprotonated, the molarequivalents of non-deprotonated beta-hydroxybutyric acid would be lessthan 5, and the molar equivalents of beta-hydroxybutyrate anions wouldbe greater than 95. The extent of deprotonation of beta-hydroxybutyricacid in solution is related to solution pH.

Whether beta-hydroxybutyrate is the R- or S-enantiomer depends on thetetrahedral orientation of the hydroxy on the 3-carbon (beta-carbon) inrelationship to the planar carboxyl group.

Beta-hydroxybutyrate, typically R-beta-hydroxybutyrate, which is theendogenous form produced by mammals, can be utilized by a patient's bodyas a fuel source during instances of low glucose levels in the subjector when a patient's body is supplemented with a usable form ofbeta-hydroxybutyrate. Beta-hydroxybutyrate is commonly referred to as a“ketone body.”

As used herein, a “ketogenic composition” is formulated to increaseketone body level in a subject, including inducing and/or sustaining astate of elevated ketone bodies at a desired level, such as ketosis, ina subject to which it is administered.

As used herein, “subject” or “patient” refers to members of the animalkingdom, including mammals, such as but not limited to, humans and otherprimates; rodents, fish, reptiles, and birds. The subject may be anyanimal requiring therapy, treatment, or prophylaxis, or any animalsuspected of requiring therapy, treatment, or prophylaxis. Prophylaxismeans that regiment is undertaken to prevent a possible occurrence, suchas where a high glucose or diabetes is identified. “Patient” and“subject” are used interchangeably herein.

“Ketosis” as used herein refers to a subject having blood ketone levels,including both enantiomers of beta-hydroxybutyrate, acetoacetate andacetone, within the range of about 0.5 mmol/L and about 16 mmol/L in asubject. Ketosis may improve mitochondrial function, decrease reactiveoxygen species production, reduce inflammation and increase the activityof neurotrophic factors. “Keto-adaptation” as used herein refers toprolonged nutritional ketosis (>1 week) to achieve a sustainednonpathological “mild ketosis” or “therapeutic ketosis.”

In some cases, “elevated ketone body level” may not mean that a subjectis in a state of “clinical ketosis” but nevertheless has an elevatedsupply of ketones for producing energy and/or for carrying out otherbeneficial effects of ketone body metabolism and signaling. For example,a subject that is “ketone adapted” may not necessarily have elevatedblood serum levels of ketone bodies but rather is able to utilizeavailable ketone bodies more rapidly compared to a subject that is not“ketone adapted.” In such case, “elevated ketone body level” can referto the total quantity and/or rate of ketone bodies being utilized by thesubject rather than blood plasma levels per se.

The term “administration” or “administering” is used herein to describethe process in which the disclosed compositions are delivered to asubject. The composition may be administered in various ways includingoral, intragastric, and parenteral (referring to intravenous andintra-arterial and other appropriate parenteral routes), among others.

The term “combination supplement” is used herein to describe thecombination of a beta-hydroxybutyrate component with one or more othersupplements and/or drugs. The beta-hydroxybutyrate component and the oneor more other supplements and/or drugs may be directly combined, such asby mixing together in the same tablet, capsule, mixed powder, or otherdosage form, or such as by placing the separate components in the samepackaging even if not directly mixed. In other embodiments, however, theseparate components need not necessarily be directly combined prior toadministration in order to fall within the scope of this disclosure. Forexample, the separate components may be administered to a subjectseparately but close enough in time (e.g., within about 8, 6, 4, 2, 1,or 0.5 hours of each other) to be considered co-administered and thuspart of a “combination supplement.”

II. Racemic R,S-Beta-Hydroxybutyrate Mixed Salt-Acid Compositions

Compositions for increasing ketone body level in a subject, includingpromoting and/or sustaining ketosis, comprise racemicR,S-beta-hydroxybutyrate mixed salt-acid compositions, including (1) 50%by enantiomeric equivalents of one or more R-beta-hydroxybutyrate saltsand 50% by enantiomeric equivalents of one or moreS-beta-hydroxybutyrate salts and (2) 50% by enantiomeric equivalents ofR-beta-hydroxybutyric acid and 50% by enantiomeric equivalents ofS-beta-hydroxybutyric acid. The composition may optionally include 50%by enantiomeric equivalents of one or more R-beta-hydroxybutyrate estersand 50% by enantiomeric equivalents of one or moreS-beta-hydroxybutyrate esters. A racemic mixture ofR,S-beta-hydroxybutyrate mixed salt-acid components can providesynergistic effects, such when used in combination with othercomponents. In such case, the combined salt and acid forms ofR,S-beta-hydroxybutyrate have acceptable pH and taste.R,S-beta-hydroxybutyrate mixed salt-acid compositions have substantialadvantages over racemic R,S-beta-hydroxybutyrate salts and esters,including increased absorption rate, increased bioavailability, lowerelectrolyte load, ease of manufacture, significantly improved taste, andreduced need for citric acid or other edible acids to obtain acomposition with neutral or acidic pH.

In some embodiments, the racemic R,S-beta-hydroxybutyrate mixedsalt-acid composition contains less than 100% of racemicR,S-beta-hydroxybutyrate salts and greater than 0% of free racemicR,S-beta-hydroxybutyric acids. Racemic R,S-beta-hydroxybutyrate mixedsalt-acid compositions may contain, on a molar basis, up to 99.9%,99.8%, 99.7%, 99.6%, 99.5%, 99.4%, 99.3%, 99.2%, 99.1%, 99%, 98.8%,98.65%, 98.5%, 98.35%, 98.2%, 98%, 97.75%, 97.5%, 97.25%, or 97%, and atleast 75%, 80%, 85%, 90%, 92%, 94%, 95%, 96%, or 97%, of total racemicR,S-beta-hydroxybutyrate salts and at least 0.1%, 0.2%, 0.3%, 0.4%,0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.2%, 1.35%, 1.5%, 1.65%, 1.8%, 2%,2.25%, 2.5%, 2.75%, or 3%, and less than 25%, 20%, 15%, 10%, 8%, 6%, 5%,4%, or 3%, of total free racemic R,S-beta-hydroxybutyric acids. Theforegoing percentages are expressed on a molar basis (e.g., moles offree R,S-beta-hydroxybutyric acids relative to total moles ofR,S-beta-hydroxybutyrate compounds in both salt and acid forms).

The racemic mixture of R-beta-hydroxybutyrate mixed salt-acid componentsand S-beta-hydroxybutyrate mixed salt-acid components containsequivalent amounts of the R-beta-hydroxybutyrate enantiomer, theendogenous form produced by a mammal, and the S-beta-hydroxybutyrateenantiomer, which is not produced or found naturally in mammals, inorder to provide enhanced ketogenic effects not possible with either ofthe enantiomers delivered alone or in enriched form.

For example, the R-beta-hydroxybutyrate enantiomer is endogenouslyproduced by a mammal during ketosis, and thus administering theR-beta-hydroxybutyrate mixed salt-acid components to a subject providesan additional quantity and/or increased blood plasma level that can berelatively immediately utilized by the body, such as for producingenergy (e.g., as an alternative energy source to glucose). The presenceof the S-beta-hydroxybutyrate mixed salt-acid components can modulatethis effect in order to provide, for example, a more controlled,gradual, and/or extended ketogenic effect compared to a compositionenriched with the R-beta-hydroxybutyrate mixed salt-acid components.

By way of further example, a racemic R,S-beta-hydroxybutyrate mixedsalt-acid composition can beneficially provide a relatively rapid boostto blood ketone body levels, primarily by way of theR-beta-hydroxybutyrate enantiomer components, in addition to arelatively more extended, sustained increase to blood ketone body levelsprimarily by way of the S-beta-hydroxybutyrate enantiomer components.Such compositions are thus capable of effectively and relatively rapidlyaiding a subject in inducing ketosis, while simultaneously providing forsustained and prolonged delivery of ketone bodies to the blood stream,wherein the R-beta-hydroxybutyrate and S-beta-hydroxybutyrate componentstogether provide synergistic ketogenic benefits to a subject.

Contrary to compositions that deliberately minimize or eliminateS-beta-hydroxybutyrate, the racemic R,S-beta-hydroxybutyrate mixedsalt-acid composition contains an equivalent quantity of theS-beta-hydroxybutyrate enantiomer, which is not endogenously produced bya mammal, in order to produce one or more desired effects in the mammal.For example, administering S-beta-hydroxybutyrate mixed salt-acidcomponents along with R-beta-hydroxybutyrate mixed salt-acid componentscan result in at least one of: (1) increased endogenous production ofR-beta-hydroxybutyrate and acetoacetate; (2) endogenous conversion ofthe S-beta-hydroxybutyrate components into one or both ofR-beta-hydroxybutyrate and acetoacetate; (3) endogenous conversion ofthe S-beta-hydroxybutyrate components into fatty acids and sterols; (4)prolonged ketosis; (5) metabolism of the S-beta-hydroxybutyratecomponents independent of conversion to R-beta-hydroxybutyrate and/oracetoacetate; (6) increased fetal development; (7) increased growthyears; (8) reduced endogenous production of acetone during ketosis; (9)signaling by the S-beta-hydroxybutyrate that modulates metabolism ofR-beta-hydroxybutyrate and glucose; (10) antioxidant activity; and (11)production of acetyl-CoA.

The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition can beused, for example, to produce one or more desired effects in thesubject, including but not limited to, appetite suppression, weightloss, fat loss, reduced blood glucose level, improved mental alertness,increased physical energy, improved cognitive function, reduction intraumatic brain injury, reduction in effect of diabetes, improvement ofneurological disorder, reduction of cancer, reduction of inflammation,anti-aging, antiglycation, reduction in epileptic seizer, improved mood,increased strength, increased muscle mass, or improved body composition.

In some embodiments, the racemic R,S-beta-hydroxybutyrate mixedsalt-acid compositions may include or be combined with a carrier, suchas a dietetically or pharmaceutically acceptable carrier. Examplescarrier or forms of the composition include powders, liquids, tablets,capsules, food products, food additives, beverages, vitamin fortifiedbeverages, beverage additives, candies, suckers, pastilles, foodsupplements, sprays, injectables, and suppositories.

Examples of R,S-beta-hydroxybutyrate salts include one or more salts ofalkali metals, alkaline earth metals, transition metals, amino acids, ormetabolites of amino acids. Examples include lithium salts, sodiumsalts, potassium salts, magnesium salts, calcium salts, zinc salts, ironsalts (as iron II and/or iron III), chromium salts, manganese salts,cobalt salts, copper salts, molybdenum salts, selenium salts, argininesalts, lysine salts, leucine salts, isoleucine salts, histidine salts,ornithine salts, citrulline salts, glutamine salts, and creatine salts.

In some embodiments, racemic R,S-beta-hydroxybutyrate mixed salt-acidcompositions may further include racemic R,S-beta-hydroxybutyrateesters, such as mono-, di-, tri-, oligo-, and polyesters. Examplesinclude mono-ester of ethanol, mono-ester of 1-propanol, mono-ester of1,2-propanediol, di-ester of 1,2-propanediol, mono-ester of1,3-propanediol, di-ester of 1,3-propanediol, mono-ester of S-, R-, orS-R-1,3-butanediol, di-ester of S-, R-, or S-R-1,3-butanediol,mono-ester of glycerin, (3S)-hydroxybutyl (3S)-hydroxybutyratemono-ester, (3R)-hydroxybutyl (3S)-hydroxybutyrate, mono-ester, di-esterof glycerin, tri-ester of glycerin, ester of acetoacetate, dimers,trimers, oligomers, and polyesters containing repeating units ofbeta-hydroxybutyrate, and complex oligomers or polymers ofbeta-hydroxybutyrate and one or more other hydroxy-carboxylic acids,such as lactic acid, citric acid, acetoacetic acid, quinic acid,shikimic acid, salicylic acid, tartaric acid, and malic acid, and/orbeta-hydroxybutyrate and or one or more diols, such as 1,3-propanedioland 1,3-butanediol, one or more polyacids, such as tartaric acid, citricacid, malic acid, succinic acid, and fumaric acid, and short chain fattyacids, such as butyric acid, valeric acid, or caproic acid.

In some embodiments, the composition may further include or be combinedwith at least one short chain fatty acid, or a mono-, di- ortriglyceride of the at least one short chain fatty acid, wherein theshort chain fatty acid has less than 6 carbons. Example short chainfatty acids include acetic acid, propionic acid, butyric acid,isobutyric acid, valeric acid, and isovaleric acid. An example shortchain triglyceride is tributyrin. Such molecules can provide protectionto the gut and improve microbiome health.

The composition may include or be combined with at least one mediumchain fatty acid, or a mono-, di- or triglyceride of the at least onemedium chain fatty acid, wherein the medium chain fatty acid has from 6to 12 carbons, preferably from 8 to 10 carbons. Example medium chainfatty acids are caproic acid, caprylic acid, capric acid, and lauricacid. Medium chain triglycerides (MCT), medium chain fatty acids, andmono- and di-glycerides are ketone body precursors that can provide anadditional source for the production of ketone bodies independent ofR-beta-hydroxybutyrate.

The composition may include or be combined with at least one long chainfatty acid, or a mono-, di- or triglyceride of the at least one longchain fatty acid, having more than 12 carbons. Examples of long-chainfatty acids include myristic acid, palmitic acid, stearic acid,arachidic acid, behenic acid, lignoceric acid, cerotic acid, omega-3fatty acids, omega-6 fatty acids, omega-7 fatty acids, and omega-9 fattyacids.

Examples and sources of the medium chain fatty acid, or an ester thereofsuch as a medium chain triglyceride, include coconut oil, coconut milkpowder, fractionated coconut oil, palm oil, palm kernel oil, caprylicacid, capric acid, isolated medium chain fatty acids, such as isolatedhexanoic acid, isolated octanoic acid, isolated decanoic acid, mediumchain triglycerides either purified or in natural form such as coconutoil, and ester derivatives of the medium chain fatty acids ethoxylatedtriglyceride, enone triglyceride derivatives, aldehyde triglyceridederivatives, monoglyceride derivatives, diglyceride derivatives, andtriglyceride derivatives, and salts of the medium chain triglycerides.Ester derivatives optionally include alkyl ester derivatives, such asmethyl, ethyl, propyl, butyl, hexyl, etc.

The administration of a racemic mixture of R-beta-hydroxybutyrate mixedsalt-acid components and S-beta-hydroxybutyrate mixed salt-acidcomponents results in a dual effect providing both: (1) an initial andrelatively immediate elevated blood level of ketone bodies; and (2) alater and relatively extended elevated blood level of ketone bodies,thereby exploiting the metabolic and physiological advantages of (1)quickly induced and (2) temporally sustained ketosis.

Raising the levels of ketone bodies in the blood through exogenoussupplementation provides a subject with greater flexibility in dietoptions as compared to methods that aim to induce and sustain ketosisbased on diet alone (e.g., based on fasting and/or limited carbohydrateintake). For example, a subject that has been administered anappropriate amount of a racemic mixture of R-beta-hydroxybutyrate mixedsalt-acid components and S-beta-hydroxybutyrate mixed salt-acidcomponents will be able to eat an occasional carbohydrate or sugar-basedfood without jeopardizing the ketogenic state and shifting back into aglucose-based metabolic state. Further, such administration facilitateseasier transitioning into a ketogenic state while reducing oreliminating the detrimental effects typically associated with enteringketosis.

In some embodiments, a ketogenic composition additionally includes atherapeutically effective amount of vitamin D₃. Vitamin D₃ is believedto work in conjunction with magnesium and calcium to promote good bonehealth and to prevent undesirable calcification of soft tissues. Inpreferred embodiments, vitamin D₃ is included in an amount such that anaverage daily dose of the ketogenic composition includes about 200 IU(“International Units”) to about 8000 IU, or about 400 IU to about 4000IU, or about 600 IU to about 3000 IU of vitamin D₃. In some embodiments,vitamin D3 is included in an amount such that an average daily dose ofthe ketogenic composition includes about 5 μg to about 200 μg, or about10 μg to about 100 μg, or about 15 μg to about 75 μg of vitamin D₃.

Some embodiments also include one or more additional ketone precursorsor supplements. These additional ketone precursors or supplements mightinclude acetoacetate, ketone esters, and/or other compounds that cause arise in blood ketone levels without adding more electrolytes to thebloodstream. Acetoacetate can be provided in salt form, ester form, acidform, and combinations thereof. Other additives include metabolites thatenhance the effect or transport of ketone bodies into mitochondria,caffeine, theobromine, and nootropics, such as L-alphaglycerylphosphorylcholine (“alpha GPC”).

The composition may include flavoring agents that help mask theoccasionally poor taste of beta-hydroxybutyrate compounds (particularlywhen provided in a non-salt form). These include essential oils, such aspeppermint, natural and artificial sweeteners, and other flavorantsknown in the art.

In some embodiments, ketogenic compositions may further include one ormore additional components configured to lower the hygroscopicity of thecomposition. For example, various anticaking agents, flow agents, and/ormoisture absorbers, in types and amounts that are safe for consumption,may be included. Such additional components may include one or more ofan aluminosilicate, ferrocyanide, carbonate or bicarbonate salt,silicate (e.g., sodium or calcium silicate), silica, phosphate salt(e.g., di- or tricalcium phosphate), talc, powdered cellulose, calciumcarbonate, and the like.

III. Stacking of Racemic R,S-Beta-Hydroxybutyrate Compounds

As described above, the racemic R,S-beta-hydroxybutyrate mixed salt-acidcompositions described herein may be provided in three general forms:(1) racemic R,S-beta-hydroxybutyrate salt(s), (2) racemicR,S-beta-hydroxybutyric acid, and optionally (3) racemicR,S-beta-hydroxybutyrate ester(s). The compositions described herein maybe provided in “stacked” mixtures combining at least salt and acid formsand optionally ester forms

Each of the different forms has its own properties and its own potentialbenefits and limitations. For example, ester forms ofbeta-hydroxybutyrate typically have poor organoleptic propertiesrelative to the other forms of beta-hydroxybutyrate. That is, esterforms of beta-hydroxybutyrate are often described as having a pungenttaste and/or smell.

Salt forms of racemic R,S-beta-hydroxybutyrate are generally consideredto taste better than ester forms. However, administration of clinicallyor dietetically effective doses of racemic R,S-beta-hydroxybutyrate insalt form inherently requires administration of relatively high levelsof the corresponding cations. Sodium, for example, is often used as thecation in beta-hydroxybutyrate salts, and high levels of sodium havewell-known negative health effects. Although differentbeta-hydroxybutyrate salts having different cations may be mixed todilute the impact of a single cation, it can still be difficult toprovide effective amounts of beta-hydroxybutyrate without upsetting theelectrolyte balance in the subject/patient.

The free acid form of racemic R,S-beta-hydroxybutyrate (i.e., racemicR,S-beta-hydroxybutyric acid) is therefore utilized to form the mixedsalt-acid compositions. Because beta-hydroxybutyric acid has a pKa of4.70, it deprotonates and produces H⁺ at physiological pH. The resultingexcess acidity can cause undesirable side effects including causing oraggravating gastrointestinal issues such as ulcers or reflux.

Combining different forms of racemic R,S-beta-hydroxybutyrate isselected amounts can beneficially limit the occurrence and/or severityof these undesirable side-effects and/or can permit administration ofhigher doses of beta-hydroxybutyrate compounds. For example, abeta-hydroxybutyrate stack can deliver the same amount ofbeta-hydroxybutyrate as a single form without causing the sameoccurrence and/or severity of side-effects. Likewise, a combined formcan deliver a greater amount of beta-hydroxybutyrate than a single formbefore reaching similar occurrence and/or severity of side-effects.

This is schematically illustrated in FIGS. 1A and 1B. FIG. 1A showsdifferent beta-hydroxybutyrate doses when using a single form(formulations 1-3), a double stack (formulations 4-6), and a triplestack (formulation 7). Although individual tolerances may vary and theillustrated doses are therefore exemplary only, a typical subject willwant to avoid excessive amounts of any single form ofbeta-hydroxybutyrate in order to avoid the corresponding side effects.Accordingly, stacking different forms of beta-hydroxybutyrate allows forgreater delivery of beta-hydroxybutyrate in a dose and/or allows for ahigher dosing frequency as compared to use of the single form. Forexample, different forms of beta-hydroxybutyrate may be stacked in asingle dose to allow for greater amounts of beta-hydroxybutyrate in thedose, and/or different forms of beta-hydroxybutyrate may be taken indifferent doses throughout the day to allow for greater dosing frequencyand thus higher overall daily delivery of beta-hydroxybutyrate.

FIG. 1B shows expected relative severity of undesirable side-effectsresulting from treatment with various formulations ofbeta-hydroxybutyrate, including stacked formulations. The triple stackformulation comprising each of 1) the salt form of beta-hydroxybutyrate,2) the free acid form of beta-hydroxybutyrate (i.e., beta-hydroxybutyricacid), and 3) the ester form of beta-hydroxybutyrate is expected toallow for administration of a greater amount of beta-hydroxybutyrateand/or to have reduced side-effects as compared to a double stackcomprising only two such forms of beta-hydroxybutyrate. Both the triplestack (i.e., triple racemic stack) and the double stack (i.e., doubleracemic stack) are likewise expected to allow for administration of agreater amount of beta-hydroxybutyrate and/or to have reducedside-effects as compared to a single form comprising only one form ofbeta-hydroxybutyrate.

In other words, for a given dose of beta-hydroxybutyrate, double andtriple racemic stacks can be formulated to cause less 1) organolepticside-effects, 2) electrolyte imbalance side-effects, and/or 3) acidityside-effects as compared to the single form. For example, a single formbeta-hydroxybutyrate ester may have a threshold dosage that the typicaluser will not exceed because of the negative organoleptic side-effects,a single form beta-hydroxybutyrate salt may have a threshold dosagelimited by the recommended dietary limits of the electrolytesadministered with the salt, and a single form beta-hydroxybutyric acidmay have a threshold dosage that the typical user will not exceedbecause of the negative effects of acidity. The stacked forms ofbeta-hydroxybutyrate allow for supplementation of greater amounts ofbeta-hydroxybutyrate without passing any of the separate thresholdsrelated to organoleptic, electrolyte, or acidity side-effects.

In some embodiments, a beta-hydroxybutyrate stack includes at least twoof: (i) one or more R,S-beta-hydroxybutyrate salts; (ii)R,S-beta-hydroxybutyric acid; and (iii) one or more beta-hydroxybutyrateesters. For example, a beta-hydroxybutyrate double stack may include atleast two of components (i), (ii), and (iii) each provided at about 2%to about 98%, or about 5% to about 95%, or about, 10% to about 90%, orabout 20% to about 80%, or about 30% to about 70%, or about 40% to about60% on a molar basis of beta-hydroxybutyrate.

In some embodiments, a beta-hydroxybutyrate triple stack includes abeta-hydroxybutyrate ester at about 2% to about 96%, or about 5% toabout 90%, or about 10% to about 80%, or about 20% to about 60% on amolar basis of beta-hydroxybutyrate, includes a beta-hydroxybutyratesalt at about 2% to about 96%, or about 5% to about 90%, or about 10% toabout 80%, or about 20% to about 60% on a molar basis ofbeta-hydroxybutyrate, and includes beta-hydroxybutyric acid at about 2%to about 96%, or about 5% to about 90%, or about 10% to about 80%, orabout 20% to about 60% on a molar basis of beta-hydroxybutyrate. In someembodiments, a beta-hydroxybutyrate triple stack includes each of thethree forms of beta-hydroxybutyrate in substantially equal amounts on amolar basis of beta-hydroxybutyrate.

A stacked beta-hydroxybutyrate composition may also provide a morebeneficial digestive release profile. Each of the different forms ofbeta-hydroxybutyrate may interact somewhat differently upon ingestion.For example, the free acid form may be readily delivered to thebloodstream as a usable ketone body, beta-hydroxybutyrate from saltforms may in general take slightly longer to reach the bloodstreamdepending on the solubility characteristics of the particular salt orsalt mixture utilized, and beta-hydroxybutyrate from ester forms may ingeneral take the longest to reach the bloodstream depending on howrapidly the ester bond undergoes hydrolysis. Thus, a stackedbeta-hydroxybutyrate formulation can be tailored to provide a morepreferable release profile, such as one that combines the benefits ofmore rapid onset with the benefits of a more extended release, and/orone that provides an overall greater pharmacokinetic area under thecurve (AUC). Stacked compositions can provide for timed delivery oravailability of ketone bodies, which provides for more even bloodconcentration of ketone bodies and a significantly longer delivery“tail” of exogenous ketone bodies, such as 1-8 hours after consuming thestacked composition.

This is illustrated in FIG. 2, which compares expected release profilesof keto stack compositions (e.g., comprising the free acid and salt) toeach of the free acid, salt, and ester single forms. Because the ketostack compositions are able to provide more overall exogenous ketonebodies, and because they are provided in a plurality of different formswith different release characteristics, the overall release profile isextended and provides a larger AUC.

FIG. 2 also illustrates how a release profile may be adjusted byutilizing different relative amounts of S-beta-hydroxybutyrate andR-beta-hydroxybutyrate. As illustrated, the beta-hydroxybutyrate in the“R Stack” is comprised of R-beta-hydroxybutyrate, while the “R/S Stack”contains a racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate, which flattens and extends the release profile.

IV. Combination Supplements

The ketogenic compositions described herein may be beneficially combinedwith one or more other dietetically and/or pharmaceutically acceptablesupplements/drugs to form a combination supplement. The uniqueproperties of a racemic R,S-beta-hydroxybutyrate mixed salt-acidcomposition may beneficially enhance the combination supplement ascompared to an otherwise similar combination supplement using abeta-hydroxybutyrate composition enriched in eitherR-beta-hydroxybutyrate or S-beta-hydroxybutyrate.

For example, a composition intended to increase lipolysis and/or fatoxidation (referred to herein as a “fat burner” component) may becombined with a racemic R,S-beta-hydroxybutyrate component to form acombination supplement with synergistic lipolysis and/or fat burningeffects. Without being bound to any particular theory, it is believedthat the fat burner composition is more readily utilized when combinedwith a racemic R,S-beta-hydroxybutyrate component as compared to whenutilized without a beta-hydroxybutyrate component. That is, the racemicR,S-beta-hydroxybutyrate component may function to effectively “prime”the subject for more metabolically efficient utilization of lipids. asan energy source. For example, with exogenous supplementation of aracemic R,S-beta-hydroxybutyrate mixed salt-acid composition, a subjectis likely to ramp up the enzymes and other metabolic machinery necessaryto utilize such ketone bodies (and thus stored body fat) as an energysource. The fat burner may therefore have enhanced pharmacokineticsand/or pharmacodynamics when co-administered, and thus may increaselipolysis and/or fat oxidation to levels higher than if either thebeta-hydroxybutyrate component or the fat burner were administered inisolation.

These synergistic effects of a combination supplement are believed to bemore pronounced when the beta-hydroxybutyrate component is a racemicR,S-beta-hydroxybutyrate component as opposed to being enriched witheither R-beta-hydroxybutyrate or S-beta-hydroxybutyrate. This isschematically illustrated in FIG. 3. As shown, for a combinationsupplement with a given beta-hydroxybutyrate dose, where thebeta-hydroxybutyrate component is enriched in R-beta-hydroxybutyrate,the level of fat oxidation/lipolysis is initially relatively high, butthen tapers relatively rapidly. Where the beta-hydroxybutyrate componentis enriched in S-beta-hydroxybutyrate, the level of fatoxidation/lipolysis is more extended in duration than the enrichedR-beta-hydroxybutyrate composition, but overall levels of fatoxidation/lipolysis remain relatively low throughout.

On the other hand, where the beta-hydroxybutyrate component is racemic,the R-beta-hydroxybutyrate components and S-beta-hydroxybutyratecomponents function to provide a relatively high initial level of fatoxidation/lipolysis as well as a relatively extended duration of fatoxidation/lipolysis. Though perhaps the racemic R,S-beta-hydroxybutyrateversion does not provide an initial level of fat oxidation/lipolysis ashigh as with the enriched R-beta-hydroxybutyrate version, and perhapsdoes not provide a duration of fat oxidation/lipolysis as long as withthe enriched S-beta-hydroxybutyrate version, the combined effects of theR-beta-hydroxybutyrate components and S-beta-hydroxybutyrate components,when provided in enantiomerically equivalent proportions, provide higheroverall levels of fat oxidation/lipolysis. In other words, the areaunder the curve is greater where the racemic R,S-beta-hydroxybutyratecomposition is utilized in the combination supplement as compared to theenriched R-beta-hydroxybutyrate or the enriched S-beta-hydroxybutyrate.

The fat burner component may include one or more compounds capable ofpromoting enhanced lipolysis and/or fat oxidation. For example, the fatburner component may include green tea, green tea extract (e.g., acomposition including one or more isolated green tea catechins such asepigallocatechin gallate (EGCG)), green coffee extract, conjugatedlinoleic acid (CLA), tetradecyl thioacetic acid (TTA), Coleus forskohlii(i.e., forskolin), yohimbine, rauwolscine, capsaicin, raspberry ketones(e.g., 4-(4-hydroxyphenyl) butan-2-one, p-hydroxybenzyl acetone),ephedrine, synephrine (e.g., bitter orange extract), octopamine,1,3-dimethylamylamine, higenamine, fucoxanthin, acetylcholine modulatorsand/or adenosine receptor antagonists (e.g., caffeine), nicotine, cocaleaves (e.g., teas, extracts, isolates, salts, and free bases), ursolicacid, clenbuterol, noradrenaline reuptake inhibitors (e.g., hordenine,atomoxetine), 7-oxodehydroepiandrosterone (i.e., 7-keto DHEA), thyroidhormones (e.g., triiodothyronine), and combinations thereof.

In another example, a combination supplement may include abeta-hydroxybutyrate component and a component intended to enhancemental alertness, cognition, and/or mood (referred to herein as a“nootropic” component). As with the fat burner embodiments, it isexpected that synergistic nootropic effects are greater when thebeta-hydroxybutyrate component is a racemic mixture rather than enrichedin R-beta-hydroxybutyrate or S-beta-hydroxybutyrate.

Exemplary compounds that may be included in the nootropic componentinclude catecholamine precursors such as tyrosine, L-DOPA (i.e.,L-3,4-dihydroxyphenylalanine), tryptophan, and 5-hydroxytryptophan(5-HTP), racetams such as such as piracetam, oxiracetam, and aniracetam,L-theanine, D-serine, phosphatidylserine, tolcapone, uridine,vinpocetine, norepinephrine reuptake inhibitors such as hordenine andatomoxetine, Panax ginseng, Ginkgo biloba, Rhodiola rosea, Polygalatenuifolia, Muira puama, Eschscholzia californica, Convolvuluspluricaulis, Centella asiatica, Evolvulus alsinoides, Bacopa monnieri,Epimedium herbs, Ashwagandha herbs, cyclic adenosine monophosphate(cAMP) modulators such as forskolin, stimulants such as nicotine,caffeine, and amphetamines, cholinergic compounds and/or acetylcholinemodulators such as huperzine-A, dimethylaminoethanol, choline, andalpha-glycerophosphocholine, and combinations thereof.

Combination supplements utilizing a racemic R,S-beta-hydroxybutyratecomponent may include other supplements/drugs in addition to or as analternative to the fat burner component. For example, a combinationsupplement may include one or more compounds intended to aid in one ormore of appetite suppression, weight loss, reduced blood glucose level,improved mental alertness, increased physical energy, improved cognitivefunction, reduction in traumatic brain injury, reduction in effect ofdiabetes, improvement of neurological disorder, reduction of cancer,reduction of inflammation, anti-aging, antiglycation, reduction inepileptic seizer, improved mood, increased strength, increased musclemass, or improved body composition.

In some embodiments, the ketogenic compositions can include or beadministered together with other vitamin and/or mineral supplements,such as vitamin D₃, and supplements for glucose control, such asberberine and other glucose lowering substances. It is postulated that aracemic mixture of R- and S-beta-hydroxybutyrate mixed salt-acidcomponents can provide a longer lasting glucose lowering effect alongwith other substances.

V. Administration

In some embodiments, the compositions disclosed herein can be used in amethod for increasing ketone body level, including promoting and/orsustaining ketosis, in a subject comprising administering to a subjectin need thereof a nutritionally or pharmaceutically effective amount ofone or more compositions disclosed herein. Examples of beneficialeffects of increasing ketone body level, including promoting and/orsustaining ketosis, in a subject include one or more of appetitesuppression, weight loss, fat loss, reduced blood glucose level,improved mental alertness, increased physical energy, improved cognitivefunction, reduction in traumatic brain injury, reduction in effect ofdiabetes, improvement of neurological disorder, reduction of cancer,reduction of inflammation, anti-aging, antiglycation, reduction inepileptic seizer, improved mood, increased strength, increased musclemass, or improved body composition.

In some embodiments, administering the racemic mixture ofR-beta-hydroxybutyrate mixed salt-acid components andS-beta-hydroxybutyrate mixed salt-acid components provides one or moreof increased endogenous production of R-beta-hydroxybutyrate andacetoacetate; endogenous conversion of the S-beta-hydroxybutyratecomponents into one or both of R-beta-hydroxybutyrate and acetoacetate;endogenous conversion of the S-beta-hydroxybutyrate components intofatty acids and sterols; prolonged ketosis; metabolism of theS-beta-hydroxybutyrate components independent of conversion toR-beta-hydroxybutyrate and/or acetoacetate; increased fetal development;increased growth years; reduced endogenous production of acetone duringketosis; signaling by the S-beta-hydroxybutyrate that modulatesmetabolism of R-beta-hydroxybutyrate and glucose; antioxidant activity;and production of acetyl-CoA.

Ketogenic compositions described herein may be administered to a subjectin therapeutically effective dosages and/or in frequencies to induce orsustain ketosis. In some embodiments, a single or unit dose will includea total amount of R-beta-hydroxybutyrate components andS-beta-hydroxybutyrate components ranging from about 0.5 gram to about25 grams, or about 0.75 gram to about 20 grams, or about 1 gram to about15 grams, or about 1.5 grams to about 12 grams.

The term “unit dose” refers to a dosage form that is configured todeliver a specified quantity or dose of composition or componentthereof. Example dosage forms include, but are not limited to, tablets,capsules, powders, food products, food additives, beverages (such asflavored, vitamin fortified, or non-alcoholic), beverage additives (suchas flavored, vitamin fortified, or non-alcoholic), candies, suckers,pastilles, food supplements, dietetically acceptable sprays (such asflavored mouth spray), injectables (such as an alcohol-free injectable),and suppositories. Such dosage forms may be configured to provide a fullunit dose or fraction thereof (e.g., ½, ⅓, or ¼ of a unit dose).

Another dosage form that can be used to provide a unit dose ofcomposition or component thereof is a unit dose measuring device, suchas a cup, scoop, syringe, dropper, spoon, spatula, or colonic irrigationdevice, which is configured to hold therein a measured quantity ofcomposition equaling a full unit dose or fraction thereof (e.g., ½, ⅓,or ¼ of a unit dose). For example, a bulk container, such as a carton,box, can, jar, bag, pouch, bottle, jug, or keg, containing several unitdoses of composition (e.g., 5-250 or 10-150 unit doses) can be providedto a user together with a unit dose measuring device that is configuredto provide a unit dose, or fraction thereof, of composition or componentthereof.

A kit for use in providing a composition as disclosed herein in bulkform, while providing unit doses of the composition, may comprise a bulkcontainer holding therein a quantity of composition and a unit dosemeasuring device configured to provide a unit dose, or fraction thereof,of composition or component thereof. One or more unit dose measuringdevices may be positioned inside the bulk container at the time of sale,attached to the outside of the bulk container, prepackaged with the bulkcontainer within a larger package, or provided by the seller ormanufacture for use with one or multiple bulk containers.

The kit may include instructions regarding the size of the unit dose, orfraction thereof, and the manner and frequency of administration. Theinstructions may be provided on the bulk container, prepackaged with thebulk container, placed on packaging material sold with the bulkcontainer, or otherwise provided by the seller or manufacturer (e.g., onwebsites, mailers, flyers, product literature, etc.) The instructionsfor use may include a reference on how to use the unit dose measuringdevice to properly deliver a unit dose or fraction thereof. Theinstructions may additionally or alternatively include a reference tocommon unit dose measuring devices, such as spoons, spatulas, cups, andthe like, not provided with the bulk container (e.g., in case theprovided unit dose measuring device is lost or misplaced). In such case,a kit may be constructed by the end user when following instructionsprovided on or with the bulk container, or otherwise provided by theseller regarding the product and how to properly deliver a unit dose ofcomposition, or fraction thereof.

In some embodiments, the ketogenic compositions can include or beadministered together with other supplements, such as vitamin D₃,vitamins, minerals, nootropics, and others known in the art. Examples ofvitamins, minerals and herbal supplements that can be added to theketogenic compositions include one or more of vitamin A, vitamin C,vitamin E, niacin, vitamin B6, folic acid, 5-MTHF, vitamin B12, iodine,zinc, copper, manganese, chromium, caffeine, theobromine, theacrine,methylliberine, huperzine A, epicatechins, and enzymes.

In some embodiments, the subject preferably follows a ketogenic dietthat restricts intake of carbohydrates and protein during the period ofadministration of the composition. In one example embodiment, thesubject may restrict the dietary intake to a ratio of about 65% fat,about 25% protein, and about 10% carbohydrates. The resultingtherapeutic ketosis provides a rapid and sustained keto-adaptation as ametabolic therapy for a wide range of metabolic disorders, and providesnutritional support for therapeutic fasting, weight loss, andperformance enhancement. As such, the composition is typicallyadministered once per day, twice per day, or three times per day to asubject desiring to promote and/or sustain a state of ketosis.

In a preferred embodiment, ketogenic compositions can be administered inone or more unit doses per day via oral administration in solid and/orpowdered form, such as in a powdered mixture (e.g., powder filledgelatin capsules), hard-pressed tablets, or other oral administrationroute known to those skilled in the art.

Although oral administration is preferred, other administration routesmay additionally or alternatively be utilized. For example, someembodiments may be administered as injectables (e.g., subdermal,parenteral, or intravenous). An injectable may include one or more ofmannitol, 1,3-butanediol, propylene glycol, water, Ringer's solution, anisotonic sodium chloride solution, or other suitable dispersing orwetting and suspending agents, including synthetic mono- ordiglycerides, and fatty acids, including oleic acid or Cremaphor.

Exemplary compositions for rectal administration include suppositorieswhich can contain, for example, a suitable non-irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquify, soften,and/or dissolve in the rectal cavity at body temperature to release thesupplement.

Exemplary compositions for nasal or pulmonary administration (e.g.,aerosol or inhalation provided through heating or via nebulization)include solutions in saline which can contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

In some embodiments, multiple doses of the composition are administeredover a period of time. The frequency of administration of thecomposition can vary depending on any of a variety of factors, such astiming of treatment from previous treatments, objectives of thetreatment, and the like. The duration of administration of thecomposition (e.g., the period of time over which the agent isadministered), can vary depending on any of a variety of factors,including subject response, desired effect of treatment, etc.

The amount of the composition to be administered can vary according tofactors such as the degree of susceptibility of the individual, the age,sex, and weight of the individual, idiosyncratic responses of theindividual, and the like. The “therapeutically effective amount” is thatamount necessary to promote a therapeutically effective result in vivo(i.e., therapeutic ketosis). In accordance with the present disclosure,a suitable single dose size is a dose that is capable of preventing oralleviating (reducing or eliminating) a symptom in a patient whenadministered one or more times over a suitable time period.

The amount of composition administered will depend on potency,absorption, distribution, metabolism, and excretion rates of unusedketone bodies, electrolytes, the method of administration, and theparticular disorder being treated, as well as other factors known tothose of skill in the art. The dose should be sufficient to affect adesirable response, such as a therapeutic or prophylactic responseagainst a particular disorder or condition, taking into account theseverity of the condition to be alleviated. The compounds may beadministered once, or may be divided and administered over intervals oftime. It is to be understood that administration may be adjustedaccording to individual need and professional judgment of a personadministrating or supervising the administration of the compositions.

VI. EXAMPLES

The following is a description of exemplary racemic mixtures ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate and other ketogeniccompositions useful for raising ketone levels in a subject, includinginducing and sustaining a ketogenic state in a subject to which they areadministered. It should be appreciated that the beta-hydroxybutyratecompounds described in the examples can be in the form of salts, esters,dimers, trimers, oligomers, and polymers, as discussed herein. Theimportant thing from the standpoint of the examples is the enantiomericpercentages or ratios of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate. The compositions can include a blend ofR,S-beta-hydroxybutyrate salts and the free R,S-beta-hydroxybutyricacid, to provide a desired electrolyte balance, taste and/orpharmacokinetic response. In some cases, the compositions can be a blendof salts, acid, and esters to provide a desired electrolyte balanceand/or modulation of ketosis. The compositions can also be combined withshort, medium, or long chain fatty acids, esters, glycerides, and othersupplements as disclosed herein to provide a desired level of elevatedketone bodies and other effects.

Example 1

A racemic R,S-beta-hydroxybutyrate mixed salt-acid composition isprepared by combining one or more R-beta-hydroxybutyrate salt compounds,one or more S-beta-hydroxybutyrate salt compounds, R-beta-hydroxybutyricacid, and S-beta-hydroxybutyric acid to provide 50% by enantiomericequivalents of R-beta-hydroxybutyrate mixed salt-acid components and 50%by enantiomeric equivalents of S-beta-hydroxybutyrate mixed salt-acidcomponents. The racemic R,S-beta-hydroxybutyrate mixed salt-acidcomposition contains less than 100% by molar equivalents of racemicR,S-beta-hydroxybutyrate salts and greater than 0% by molar equivalentsof free racemic R,S-beta-hydroxybutyric acids.

Because the racemic mixture includes 50% by enantiomeric equivalents ofR-beta-hydroxybutyrate mixed salt-acid compounds, the onset of ketosisis accelerated for a given dosage as compared to the same dosageenriched with S-beta-hydroxybutyrate compounds. On the other hand,because the racemic mixture includes 50% by enantiomeric equivalents ofS-beta-hydroxybutyrate mixed salt-acid compounds, the duration ofsustained ketosis is increased for a given dosage as compared to thesame dosage enriched with R-beta-hydroxybutyrate compounds.

The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition isreadily administered as a ketogenic composition, such as in powder formas a dietary supplement mixed with food or drink, in the form of one ormore capsules or tablets, or in liquid form such as a mouth spray.

Example 2

The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition ofExample 1 is formulated to provide up to 99.9%, 99.8%, 99.7%, 99.6%,99.5%, 99.4%, 99.3%, 99.2%, 99.1%, 99%, 98.8%, 98.65%, 98.5%, 98.35%,98.2%, 98%, 97.75%, 97.5%, 97.25%, or 97%, and at least 75%, 80%, 85%,90%, 92%, 94%, 95%, 96%, or 97%, by molar equivalents of racemicR,S-beta-hydroxybutyrate salts and at least 0.1%, 0.2%, 0.3%, 0.4%,0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.2%, 1.35%, 1.5%, 1.65%, 1.8%, 2%,2.25%, 2.5%, 2.75%, or 3%, and less than 25%, 20%, 15%, 10%, 8%, 6%, 5%,4%, or 3%, by molar equivalents of free racemic R,S-beta-hydroxybutyricacids.

The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition isreadily administered as a ketogenic composition, such as in powder formas a dietary supplement mixed with food or drink, in the form of one ormore capsules or tablets, or in liquid form such as a mouth spray.

Example 3

Example 1 or Example 2 is modified by combining the racemicR,S-beta-hydroxybutyrate mixed salt-acid composition with a dietetically(i.e., nutritionally) or pharmaceutically acceptable carrier.

Example 4

Any of the foregoing examples is modified by combining the racemicR,S-beta-hydroxybutyrate mixed salt-acid composition with one or moreshort chain fatty acids, and/or one or more mono-, di- or triglyceridesthereof, such as tributyrin.

Example 5

Any of the foregoing examples is modified by combining the racemicR,S-beta-hydroxybutyrate mixed salt-acid composition with one or moremedium chain fatty acids, and/or one or more mono-, di- or triglyceridesthereof, such as MCT oil.

Example 6

Any of the foregoing examples is modified by combining the racemicR,S-beta-hydroxybutyrate mixed salt-acid composition with one or morelong chain fatty acids, and/or one or more mono-, di- or triglyceridesthereof.

Example 7

Any of the foregoing examples is modified by combining the racemicR,S-beta-hydroxybutyrate mixed salt-acid composition with one or moresupplements, such as vitamin D₃, vitamins, minerals, and others known inthe art.

Example 8

Any of the foregoing examples is modified by combining the racemicR,S-beta-hydroxybutyrate mixed salt-acid composition with one or morefat burner supplements such as green tea, green tea extract (e.g., acomposition including one or more isolated green tea catechins such asepigallocatechin gallate (EGCG)), green coffee extract, conjugatedlinoleic acid (CLA), tetradecyl thioacetic acid (TTA), Coleus forskohlii(i.e., forskolin), yohimbine, rauwolscine, capsaicin, raspberry ketones(e.g., 4-(4-hydroxyphenyl) butan-2-one, p-hydroxybenzyl acetone),ephedrine, synephrine (e.g., bitter orange extract), octopamine,1,3-dimethylamylamine, higenamine, fucoxanthin, acetylcholine modulatorsand/or adenosine receptor antagonists (e.g., caffeine), nicotine, cocaleaf derivative, ursolic acid, clenbuterol, noradrenaline reuptakeinhibitors (e.g., hordenine, atomoxetine), 7-oxodehydroepiandrosterone(i.e., 7-keto DHEA), thyroid hormones (e.g., triiodothyronine), andcombinations thereof.

The resulting combined supplement is expected to provide greaterlipolysis and/or fat oxidation effects than a similar dose utilizing abeta-hydroxybutyrate component enriched in R-beta-hydroxybutyrate orenriched in S-beta-hydroxybutyrate.

Example 9

Any of the foregoing examples is modified by combining the racemicR,S-beta-hydroxybutyrate mixed salt-acid composition with one or morenootropic supplements such as tyrosine, L-DOPA (i.e.,L-3,4-dihydroxyphenylalanine), tryptophan, and 5-hydroxytryptophan(5-HTP), racetams such as such as piracetam, oxiracetam, and aniracetam,L-theanine, D-serine, phosphatidylserine, tolcapone, uridine,vinpocetine, norepinephrine reuptake inhibitors such as hordenine andatomoxetine, Panax ginseng, Ginkgo biloba, Rhodiola rosea, Polygalatenuifolia, Muira puama, Eschscholzia californica, Convolvuluspluricaulis, Centella asiatica, Evolvulus alsinoides, Bacopa monnieri,Epimedium herbs, Ashwagandha herbs, cyclic adenosine monophosphate(cAMP) modulators such as forskolin, stimulants such as nicotine,caffeine, and amphetamines, cholinergic compounds and/or acetylcholinemodulators such as huperzine-A, dimethylaminoethanol, choline, andalpha-glycerophosphocholine, and combinations thereof.

The resulting combined supplement is expected to provide greatercognition, alertness, and/or mood effects than a similar dose utilizinga beta-hydroxybutyrate component enriched in R-beta-hydroxybutyrate orenriched in S-beta-hydroxybutyrate.

The present invention may be embodied in other specific forms withoutdeparting from its spirit or essential characteristics. The describedembodiments are to be considered in all respects only as illustrativeand not restrictive. The scope of the invention is, therefore, indicatedby the appended claims rather than by the foregoing description. Allchanges which come within the meaning and range of equivalency of theclaims are to be embraced within their scope.

1. A racemic R,S-beta-hydroxybutyrate mixed salt-acid composition forincreasing ketone level in a subject, comprising: a racemic mixture ofbeta-hydroxybutyric acids containing 50% by enantiomeric equivalents ofR-beta-hydroxybutyric acid and 50% by enantiomeric equivalents ofS-beta-hydroxybutyric acid; and a racemic mixture ofbeta-hydroxybutyrate salts containing 50% by enantiomeric equivalents ofone or more R-beta-hydroxybutyrate salts and 50% by enantiomericequivalents of one or more S-beta-hydroxybutyrate salts, wherein thebeta-hydroxybutyrate salts are selected from: sodiumR-beta-hydroxybutyrate; potassium R-beta-hydroxybutyrate; calciumR-beta-hydroxybutyrate; magnesium R-beta-hydroxybutyrate; sodiumS-beta-hydroxybutyrate; potassium S-beta-hydroxybutyrate; calciumS-beta-hydroxybutyrate; and magnesium S-beta-hydroxybutyrate; whereinthe composition is in solid and/or powder form.
 2. The racemicR,S-beta-hydroxybutyrate mixed salt-acid composition of claim 1, whereinthe composition comprises at least two of: a racemic mixture of sodiumR-beta-hydroxybutyrate and sodium S-beta-hydroxybutyrate; a racemicmixture of potassium R-beta-hydroxybutyrate and potassiumS-beta-hydroxybutyrate; a racemic mixture of calciumR-beta-hydroxybutyrate and calcium S-beta-hydroxybutyrate; or a racemicmixture of magnesium R-beta-hydroxybutyrate and magnesiumS-beta-hydroxybutyrate.
 3. The racemic R,S-beta-hydroxybutyrate mixedsalt-acid composition of claim 1, wherein the composition comprises 75%to 99.9% by molar equivalents of the racemic mixture ofbeta-hydroxybutyrate salts and 25% to 0.1% by molar equivalents of theracemic mixture of beta-hydroxybutyric acids.
 4. The racemicR,S-beta-hydroxybutyrate mixed salt-acid composition of claim 1, whereinthe composition comprises 80% to 99.7% by molar equivalents of theracemic mixture of beta-hydroxybutyrate salts and 20% to 0.3% by molarequivalents of the racemic mixture of beta-hydroxybutyric acids.
 5. Theracemic R,S-beta-hydroxybutyrate mixed salt-acid composition of claim 1,wherein the composition comprises 85% to 99.5% by molar equivalents ofthe racemic mixture of beta-hydroxybutyrate salts and 15% to 0.5% bymolar equivalents of the racemic mixture of beta-hydroxybutyric acids.6. The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition ofclaim 1, wherein the composition comprises 90% to 99% by molarequivalents of the racemic mixture of beta-hydroxybutyrate salts and 10%to 1% by molar equivalents of the racemic mixture of beta-hydroxybutyricacids.
 7. The racemic R,S-beta-hydroxybutyrate mixed salt-acidcomposition of claim 1, further comprising at least one short chainfatty acid having less than 6 carbons, or a mono-, di- or triglycerideof the at least one short chain fatty acid.
 8. The racemicR,S-beta-hydroxybutyrate mixed salt-acid composition of claim 1, furthercomprising at least one medium chain fatty acid having from 6 to 12carbons, such as from 8 to 10 carbons, or a mono-, di- or triglycerideof the at least one medium chain fatty acid.
 9. The racemicR,S-beta-hydroxybutyrate mixed salt-acid composition of claim 1, furthercomprising at least one of: a fat burner supplement for increasinglipolysis and/or fat oxidation; or a nootropic supplement for increasingcognitive performance, alertness, and/or mood.
 10. The racemicR,S-beta-hydroxybutyrate mixed salt-acid composition of claim 9, whereinthe one or more fat burner supplements are selected from the groupconsisting of green tea, green tea extract, isolated green teacatechins, epigallocatechin gallate (EGCG), green coffee extract,conjugated linoleic acid (CLA), tetradecyl thioacetic acid (TTA), Coleusforskohlii, yohimbine, rauwolscine, capsaicin, raspberry ketones,4-(4-hydroxyphenyl) butan-2-one, p-hydroxybenzyl acetone, ephedrine,synephrine, octopamine, 1,3-dimethylamylamine, higenamine, fucoxanthin,acetylcholine modulators and/or adenosine receptor antagonists,caffeine, nicotine, coca leaf derivatives, ursolic acid, clenbuterol,noradrenaline reuptake inhibitors, hordenine, atomoxetine,7-oxodehydroepiandrosterone, triiodothyronine, and combinations thereof.11. The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition ofclaim 9, wherein the one or more nootropic compounds are selected fromthe group consisting of tyrosine, L-DOPA, tryptophan,5-hydroxytryptophan, racetams, piracetam, oxiracetam, aniracetam,L-theanine, D-serine, phosphatidylserine, tolcapone, uridine,vinpocetine, norepinephrine reuptake inhibitors, hordenine, atomoxetine,Panax ginseng, Ginkgo biloba, Rhodiola rosea, Polygala tenuifolia, Muirapuama, Eschscholzia californica, Convolvulus pluricaulis, Centellaasiatica, Evolvulus alsinoides, Bacopa monnieri, Epimedium herbs,Ashwagandha herbs, cyclic adenosine monophosphate (cAMP) modulators,forskolin, nicotine, caffeine, amphetamines, coca leaf derivatives,cholinergic compounds, acetylcholine modulators, huperzine-A,dimethylaminoethanol, choline, alpha-glycerophosphocholine, andcombinations thereof.
 12. The racemic R,S-beta-hydroxybutyrate mixedsalt-acid composition of claim 1, further comprising a racemic mixtureof one or more R-beta-hydroxybutyrate esters and one or moreS-beta-hydroxybutyrate esters.
 13. A method for increasing ketone bodylevel in a subject, comprising administering to a subject in needthereof a nutritionally or pharmaceutically effective amount of thecomposition of claim 1, wherein increasing ketone body level in thesubject results in one or more of appetite suppression, weight loss, fatloss, reduced blood glucose level, improved mental alertness, anxiolyticeffects (anti-anxiety), faster reaction time, increased physical energy,improved cognitive function, reduction in traumatic brain injury,reduction in effect of diabetes, improvement of neurological disorder,reduction of cancer, reduction of inflammation, anti-aging,antiglycation, reduction in epileptic seizer, improved mood, increasedstrength, increased muscle mass, or improved body composition; andS-beta-hydroxybutyrate components in the composition cause at least oneof: increased endogenous production of R-beta-hydroxybutyrate andacetoacetate; endogenous conversion of the S-beta-hydroxybutyratecomponents into one or both of R-beta-hydroxybutyrate and acetoacetate;endogenous conversion of the S-beta-hydroxybutyrate components intofatty acids and sterols; prolonged ketosis; metabolism of theS-beta-hydroxybutyrate components independent of conversion toR-beta-hydroxybutyrate and/or acetoacetate; increased fetal development;increased growth years; reduced endogenous production of acetone duringketosis; signaling by the S-beta-hydroxybutyrate components thatmodulates metabolism of R-beta-hydroxybutyrate and glucose; antioxidantactivity; or production of acetyl-CoA.
 14. A racemicR,S-beta-hydroxybutyrate mixed salt-acid composition for increasingketone level in a subject, comprising: a racemic mixture ofbeta-hydroxybutyric acids containing 50% by enantiomeric equivalents ofR-beta-hydroxybutyric acid and 50% by enantiomeric equivalents ofS-beta-hydroxybutyric acid; and a racemic mixture ofbeta-hydroxybutyrate salts containing 50% by enantiomeric equivalents ofone or more R-beta-hydroxybutyrate salts and 50% by enantiomericequivalents of one or more S-beta-hydroxybutyrate salts, wherein thebeta-hydroxybutyrate salts are selected from: sodiumR-beta-hydroxybutyrate; potassium R-beta-hydroxybutyrate; calciumR-beta-hydroxybutyrate; magnesium R-beta-hydroxybutyrate; sodiumS-beta-hydroxybutyrate; potassium S-beta-hydroxybutyrate; calciumS-beta-hydroxybutyrate; and magnesium S-beta-hydroxybutyrate; whereinthe composition is provided as or in a tablet, capsule, powder, foodproduct, food additive, flavored beverage, vitamin fortified beverage,non-alcoholic beverage, flavored beverage additive, vitamin fortifiedbeverage additive, non-alcoholic beverage additive, candy, sucker,pastille, food supplement, flavored mouth spray, or suppository.
 15. Theracemic R,S-beta-hydroxybutyrate mixed salt-acid composition of claim14, wherein the composition comprises 75% to 99.9% by molar equivalentsof the racemic mixture of beta-hydroxybutyrate salts and 25% to 0.1% bymolar equivalents of the racemic mixture of beta-hydroxybutyric acids.16. A racemic R,S-beta-hydroxybutyrate mixed salt-acid composition forincreasing ketone level in a subject, comprising: a dietetically orpharmaceutically acceptable carrier selected from the group consistingof tablet, capsule, powder, food product, food additive, flavoredbeverage, vitamin fortified beverage, non-alcoholic beverage, flavoredbeverage additive, vitamin fortified beverage additive, non-alcoholicbeverage additive, candy, sucker, pastille, food supplement, flavoredmouth spray, and suppository; a racemic mixture of beta-hydroxybutyricacids containing 50% by enantiomeric equivalents ofR-beta-hydroxybutyric acid and 50% by enantiomeric equivalents ofS-beta-hydroxybutyric acid; and a racemic mixture ofbeta-hydroxybutyrate salts containing 50% by enantiomeric equivalents ofone or more R-beta-hydroxybutyrate salts and 50% by enantiomericequivalents of one or more S-beta-hydroxybutyrate salts, wherein thebeta-hydroxybutyrate salts are selected from: sodiumR-beta-hydroxybutyrate; potassium R-beta-hydroxybutyrate; calciumR-beta-hydroxybutyrate; magnesium R-beta-hydroxybutyrate; sodiumS-beta-hydroxybutyrate; potassium S-beta-hydroxybutyrate; calciumS-beta-hydroxybutyrate; and magnesium S-beta-hydroxybutyrate.
 17. Theracemic R,S-beta-hydroxybutyrate mixed salt-acid composition of claim16, wherein the composition comprises 75% to 99.9% by molar equivalentsof the racemic mixture of beta-hydroxybutyrate salts and 25% to 0.1% bymolar equivalents of the racemic mixture of beta-hydroxybutyric acids.18. A kit for administering ketone bodies to a subject, comprising: theracemic R,S-beta-hydroxybutyrate mixed salt-acid composition of claim 1;a container in which the composition is placed; and a measuring deviceconfigured to hold therein a unit dose, or fraction thereof, of thecomposition, wherein a unit dose of the composition contains about 0.5 gto about 25 g of R-beta-hydroxybutyrate compounds.
 19. The kit of claim18, wherein the container is selected from the group consisting ofcarton, box, can, jar, bag, pouch, bottle, jug, and keg.
 20. The kit ofclaim 18, wherein the measuring device is selected from the groupconsisting of cup, scoop, syringe, dropper, spatula, spoon, and colonicirrigation device.